Centre for Research in Biomolecular Interactions present a gues lecturer, Dr. Alan Cochrane from Department of Molecular Genetics, University of Toronto.

Silencing HIV-1: Factors Controlling HIV-1 Expression Post-integration

Abstract:

Following integration of the viral DNA into host cell DNA, expression of the HIV-1 genome is dependent the appropriate balance of processing of its RNA. From a single 9 kb primary transcript more than 30 mRNAs are generated through the use of alternative splicing. Control of viral RNA processing is controlled in large part by host factors belonging to the hnRNP and SR protein families. In addition, to controlling viral RNA processing, HIV-1 also has to overcome the impairment in nuclear export of its incompletely spliced RNAs. Export of its incompletely spliced RNAs is achieved through the action of virally encoded Rev which interacts with these viral RNAs to mediate their export through the exportin-1 export pathway. To identify key host factors involved in regulating these processes and to develop new strategies to impair HIV-1 replication, my laboratory has been using si/shRNAs to examine the effect of depleting individual host factors on HIV-1 expression and investigating the underlying mechanism of the effects observed. These studies have identified several members of the hnRNP and SR families that play critical roles in various stages of HIV-1 gene expression. In parallel, screening of small molecule libraries has been performed to identify inhibitors of these viral RNA processing pathways. Efforts to date have identified both digoxin and chlorhexidine as potent modulators of viral RNA splicing that result in significant suppression of HIV-1 gene expression. Together, these approaches are providing valuable insights into new targets for anti-HIV therapy and identified compounds, currently in use in humans, that could form the basis for alternative strategies to control this infection.

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